High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects.
High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects.
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DOI：
10.18632/oncotarget.597
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Saunthararajah Y
中科院分区：
文献类型：
--
作者：
Ebrahem Q;Mahfouz RZ;Ng KP;Saunthararajah Y
我们首次证明，在一个表达高水平胞苷脱氨酶(CDA)的器官中的避难所是癌细胞对胞苷类似物耐药的一种机制。这一机制可以解释为什么从历史上看，胞苷类似物尽管在体外有效，但对嗜肝肿瘤的化疗并不成功。重要的是，通过将胞苷类似物与胞苷脱氨酶抑制剂(四氢尿苷)相结合，这种耐药机制可以很容易地逆转，而不会增加对敏感器官的毒性。具体地说，CDA能迅速将胞苷类似物代谢成不活跃的尿苷类似物。因此，为了确定对高表达CDA的器官(如肝脏)中的癌细胞的保护/保护是否是一种耐药机制，我们利用了对胞苷类似物地西他滨的表观遗传治疗作用敏感的小鼠骨髓癌异种移植模型。用地西他滨(皮下0.2 mg/kg，每周2次)治疗荷瘤小鼠，中位生存期增加一倍，并显著降低肝外肿瘤负担，但肝脏肿瘤负担仍然很大，动物最终屈服于此。联合使用临床相关的CDA抑制剂(四氢尿苷)和较小剂量的地西他滨(皮下注射0.1 mg/kg 2X/周)可显著减轻肝肿瘤的负担，而不需要进行血细胞计数或骨髓毒性试验，并可进一步提高存活率。总之，在富含CDA的器官中避难所是一种机制，通过这种机制，原本易感的癌细胞可以抵抗地西他滨表观遗传治疗的效果。通过将四氢尿苷与较小剂量的地西他滨联合使用，这种保护可以逆转，而不会增加骨髓毒性。
We document for the first time that sanctuary in an organ which expresses high levels of the enzyme cytidine deaminase (CDA) is a mechanism of cancer cell resistance to cytidine analogues. This mechanism could explain why historically, cytidine analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy in vitro. Importantly, this mechanism of resistance can be readily reversed, without increasing toxicity to sensitive organs, by combining cytidine analogue with an inhibitor of cytidine deaminase (tetrahydrouridine). Specifically, CDA rapidly metabolizes cytidine analogues into inactive uridine counterparts. Hence, to determine if sheltering/protection of cancer cells in organs which express high levels of CDA (e.g., liver) is a mechanism of resistance, we utilized a murine xenotransplant model of myeloid cancer that is sensitive to epigenetic therapeutic effects of the cytidine analogue decitabine in vitro and hepato-tropic in vivo. Treatment of tumor-bearing mice with decitabine (subcutaneous 0.2mg/kg 2X/week) doubled median survival and significantly decreased extra-hepatic tumor burden, but hepatic tumor burden remained substantial, to which the animals eventually succumbed. Combining a clinically-relevant inhibitor of CDA (tetrahydrouridine) with a lower dose of decitabine (subcutaneous 0.1mg/kg 2X/week) markedly decreased liver tumor burden without blood count or bone marrow evidence of myelotoxicity, and with further improvement in survival. In conclusion, sanctuary in a CDA-rich organ is a mechanism by which otherwise susceptible cancer cells can resist the effects of decitabine epigenetic therapy. This protection can be reversed without increasing myelotoxicity by combining tetrahydrouridine with a lower dose of decitabine.
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